End-stage renal disease (ESRD) is a major public health problem in the US and is increasing in incidence and prevalence, primarily due to an aging population with a higher incidence of diabetes and hypertension. A major determinant of the quality of life in the elderly is the level of cognitive function;however this has not been well studied in ESRD. We recently received an R21 grant to obtain preliminary data on cognitive function in hemodialysis patients. In the current application we extend the number of participants involved in the study and also focus on longitudinal follow-up of these patients. The goal is to prospectively evaluate the range of cognitive function and risk factors for development of cognitive impairment in hemodialysis patients. Our primary hypothesis is that there is a high prevalence of cognitive impairment as well as structural brain abnormalities in hemodialysis patients, and that total plasma homocysteine (tHcy), oxidative stress, inflammation and endothelial dysfunction are associated with cognitive impairment via a pathway of cerebrovascular disease. Our primary aims are 1: to assemble a cohort of 312 hemodialysis patients from 5 Massachusetts Dialysis Clinic Incorporated (DCI) units, assess the range of cognitive function, and compare the results with age-, gender- and education-matched normative data from the general population, and 2: to prospectively assess for change in cognitive function and risk factors for this change in 240, 184 and 115 patients in 1, 2 and 3 yrs of follow-up, respectively. The secondary aim is to perform brain MRI in 50 subjects, to evaluate the prevalence of atrophy, large and small vessel disease, and decreased diffusion anisitropy, and to compare the results with several control groups. The R21 phase has confirmed the feasibility of successfully completing this project. The principal investigator has assembled a multidisciplinary research team consisting of experts in each of their respective fields. The most up-to-date biological assays will be used to evaluate the primary risk factors of interest. Validated neurocognitive assessment instruments will be used to assess the primary outcome of cognitive function. Plans have been developed for evaluation of generalizability, and statistical analyses suggest adequate power to evaluate each of the primary aims. Cognitive impairment adversely affects the quality of life of the aging population. There are insufficient data on cognitive function in dialysis patients, and cognitive impairment will become more of a problem as the dialysis population ages. Evaluating the prevalence of as well as potential risk factors for development or progression of cognitive impairment in dialysis patients is essential to provide clues as to potential interventions that may reduce the burden of cognitive impairment in this patient population. NARRATIVE : Cognitive impairment adversely affects the quality of life of the aging population. There are insufficient data on cognitive function in dialysis patients, and cognitive impairment will become more of a problem as the dialysis population ages. Evaluating the prevalence of as well as potential risk factors for development or progression of cognitive impairment in dialysis patients is essential to provide clues as to potential interventions that may reduce the burden of cognitive impairment in this patient population.